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Abstract Background Ionizing radiation (IR), including radiotherapy, can exert lasting harm on living organisms. While liposaccharide (LPS) offers resistance to radiation damage, it also induces toxic responses. Thankfully, an LPS analogue called N-formylmethionine-leucyl-phenylalanine (fMLP) holds the potential to mitigate this toxicity, offering hope for radiation protection. Methods Survival of C57BL/6 mice exposed to IR after administration with fMLP/LPS/WR-2721 or saline was recorded. Cell viability and apoptosis assay of bone marrow (BMC), spleen and small intestinal epithelial (HIECs) cells were tested by Cell Counting Kit-8 (CCK-8) and flow cytometry assay. Tissue damage was evaluated by Hematoxilin and Eosin (H&E), Ki-67, and TUNEL staining. RNA sequencing was performed to reveal potential mechanisms of fMLP-mediated radiation protection. Flow cytometry and western blot were performed to verify the radiation protection mechanism of fMLP on the cell cycle. Results The survival rates of C57BL/6 mice exposed to ionizing radiation after administering fMLP increased. fMLP demonstrated low toxicity in vitro and in vivo, maintaining cell viability and mitigating radiation-induced apoptosis. Moreover, it protected against tissue damage in the hematopoietic and intestinal system. RNA sequencing shed light on fMLP’s potential mechanism, suggesting its role in modulating innate immunity and cell cycling. This was evidenced by its ability to reverse radiation-induced G2/M phase arrests in HIECs. Conclusion fMLP serves as a promising radioprotective agent, preserving cells and radiosensitive tissues from IR. Through its influence on the cell cycle, particularly reversing radiation-induced arrest in G2/M phases, fMLP offers protection against IR’s detrimental effects.

Background: Microvascular invasion (MVI) is associated with an unfavorable prognosis and early recurrence of hepatocellular carcinoma (HCC), which is the crucial pathological hallmark of immunotherapy. While microvascular invasion (MVI) in hepatocellular carcinoma (HCC) currently lacks a detailed single-cell analysis of the tumor microenvironment (TME), it holds significant promise for immunotherapy using immune checkpoint inhibitors (ICI). Methods: We performed single-cell RNA sequencing (scRNA-seq) on 3 MVI positive (MVIP) and 14 MVI-negative (MVIN) tumor tissues, as well as their paired adjacent non-tumoral tissues. Results: We identified SPP1+ macrophages and CD4+ proliferative T cells as intertumoral populations critical for the formation of cold tumors and immunosuppressive environments in MVI-positive patients and verified their prognostic value in correlation with MVIP HCC patients. Additionally, we identified SPP1+ dominated interactions between SPP1+ macrophages and the immunosuppressive T population as contributors to MVI destruction and tumorigenesis. Conclusions: We provide a comprehensive single-cell atlas of HCC patients with MVI, shedding light on the immunosuppressive ecosystem and upregulated signaling associated with MVI. These findings demonstrate that intercellular mechanisms drive MVI and provide a potential immunotherapeutic target for HCC patients with HCC and underlying MVI.

ABSTRACTChimeric antigen receptor (CAR) T cells have demonstrated outstanding therapeutic success in hematological malignancies. Yet, their efficacy against solid tumors remains constrained due to inadequate infiltration of cytotoxic T and CAR-T cells in the tumor microenvironment (TME), a factor correlated with poor prognosis in patients with solid tumors. To overcome this limitation, we engineered CAR-T cells to secrete CXCL10 and IL15 (10 × 15 CAR-T), which sustain T cell viability and enhance their recruitment, thereby amplifying the long-term cytotoxic capacity of CAR-T cells in vitro. In a xenograft model employing NUGC4-T21 cells, mice receiving 10 × 15 CAR-T cells showed superior tumor reduction and extended survival rates compared to those treated with second-generation CAR-T cells. Histopathological evaluations indicated a pronounced increase in cytotoxic T cell accumulation in the TME post 10 × 15 CAR-T cell treatment. Therefore, the synergistic secretion of CXCL10 and IL15 in these CAR-T cells enhances T cell recruitment and adaptability within tumor tissues, improving tumor control. This approach may offer a promising strategy for advancing CAR-T therapies in the treatment of solid tumors.

Tumor-infiltrating immune cells (TICs) play a central role in the tumor microenvironment, which can reflect the host anti-tumor immune response. However, few studies have explored TICs in predicting the prognosis of lung adenocarcinoma (LUAD). In our study, we enrolled 2470 LUAD patients from TCGA and GEO databases, and the normalized enrichment scores for 65 immune cell types were quantified for each patient. An immune-related risk score (IRRS) was built on the basis of 17 selected TICs using LASSO regression analysis, and the results showed that high-risk patients were correlated with shorter survival time for the LUAD cohorts. Correlation analyses between IRRS and clinical characteristics were also evaluated to validate the clinical use of IRRS. In addition, we analyzed the differences in the distribution of immune cell infiltration and immunoregulatory gene expression, which may facilitate individual immunotherapy. Based on the above result, we conclude that IRRS can act as a powerful predictor for risk stratification and prognosis prediction, and may facilitate the decision-making process for LUAD patients.

Abstract Background Immunotherapy has transformed cancer treatment patterns for advanced hepatocellular carcinoma (aHCC) in recent years. Therefore, the identification of predictive biomarkers has important clinical implications. Methods We collected medical records from 117 aHCC patients treated with anti-PD-1 antibody. Kaplan-Meier analysis and Cox proportional hazard regression were used to evaluate the association between peripheral blood biomarkers and overall survival (OS) and progression-free survival (PFS). Finally, the prognostic nomogram was constructed. Results The mPFS and mOS were 7.0 months and 18.7 months, respectively. According to Kaplan-Meier analysis and Cox regression analysis, we regarded the treatment regimen (p = 0.020), hemoglobin (Hb) at 6-week (p = 0.042), neutrophil-to-lymphocyte ratio (NLR) at 6-week (p

Abstract Background Peripheral blood‐derived natural killer (NK) cells spontaneously lyse tumor cells without prior sensitization. However, NK cells in peripheral blood (PBNK cells) are in a resting state and exhibit inhibitory phenotypes and impaired cytotoxicity. Thus, strengthening the cytotoxic effector function of PBNK cells and improving NK cell expansion in vitro for a convenient allogeneic therapy are essential. Materials and Methods Pure cytokine activation and expansion of NK cells (super NK [SNK]) from peripheral blood mononuclear cells were studied. Markers of activated and inhibited NK cells and cytokine secretion by NK cells were examined using flow cytometry. NK cell antitumor activity in vitro was assessed using lactate dehydrogenase (LDH) cytotoxicity assay and an Incucyte real‐time imaging system. Additionally, the function of SNK cells against ascites caused by ovarian cancer in NOD‐Prkdc(em26Cd52)il2rg(em26Cd22)/Nju (NCG) mice was determined. In a further investigation of the differences between PBNK and SNK, the mRNA of both cells was sequenced and analyzed. Results Human peripheral blood mononuclear cells showed selective NK cell expansion upon cytokine activation and culture. Both SNK and PBNK cells expressed activation markers, but at different levels, and SNK cells secreted more cytokines related to cytotoxicity than PBNK cells did. Accordingly, SNK cells exhibited strong antitumor activity ex vivo and improved NCG mice survival after intraperitoneal ovarian cancer transplantation. Mechanistically, SNK cells expressed more genes associated with nucleotide metabolism, fatty acid, and ATP metabolism than PBNK cells. Conclusion SNK cells derived from peripheral blood mononuclear cells have sufficiently activated mature characteristics and high antitumor activity, rendering them a highly promising and essential therapeutic approach for cancer treatment.

Purpose: This study aimed to screen biomarkers to predict the efficacy of programmed cell death 1 (PD-1) blockade immunotherapy combined with chemotherapy as neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC). Methods: In the first stage of the study, the baseline concentrations of 40 tumor-related chemokines in the serum samples of 50 patients were measured to screen for possible biomarkers. We investigated whether the baseline concentration of the selected chemokine was related to the therapeutic outcomes and tumor microenvironment states of patients treated with the therapy. In the second stage, the reliability of the selected biomarkers was retested in 34 patients. Results: The baseline concentration of macrophage migration inhibitory factor (MIF) was negatively correlated with disease-free survival (DFS) and overall survival (OS) in patients treated with the therapy. In addition, a low baseline expression level of MIF is related to a better tumor microenvironment for the treatment of ESCC. A secondary finding was that effective treatment decreased the serum concentration of MIF. Conclusion: Baseline MIF levels were negatively correlated with neoadjuvant therapy efficacy. Thus, MIF may serve as a predictive biomarker for this therapy. The accuracy of the prediction could be improved if the serum concentration of MIF is measured again after the patient received several weeks of treatment.

Summary: Background: Immune checkpoint inhibitors combined with chemotherapy as a neoadjuvant therapy have been applied to the treatment of esophageal squamous cell carcinoma (ESCC). However, the optimal regimen needs to be further explored, particularly for older patients, and the mechanisms by which the immune checkpoint inhibitor combined with chemotherapy modulates the evolution of ESCC are unknown. Methods: In this single-arm phase 2 trial, patients with resectable (stage II/III/IV without metastasis) ESCC were enrolled and received nanoparticle albumin-bound (nab) paclitaxel for two cycles and oral S-1 for 2 weeks, combined with intravenous toripalimab for two cycles before surgery. Combination postoperative adjuvant therapy was administered. The primary outcome was the major pathological response (MPR). Secondary outcomes included pathological complete response (pCR), overall response rate (ORR), disease control rate (DCR), disease-free survival (DFS), overall survival (OS), improvement in Stooler's dysphagia score and degree of daily living ability (dADL). Biopsies and plasma pre- and post-neoadjuvant therapy were performed using whole-exome sequencing, transcriptome sequencing, immunohistochemistry (IHC) for PD-L1, multiplex immunofluorescence (mIF) and proximity extension assay technology (PEA) for 92 proteins. Findings: From November 2019 to July 2021, 60 patients were enrolled. After neoadjuvant therapy, R0 resection was achieved in 55 (98.21%) patients. MPR was identified in 27 patients (49.09%), and 16 patients (29.09%) achieved pCR. Patients with PR, SD and PD were 37 (61.67%), 21 (35.00%) and 2 (3.33%), respectively. The overall staging, Stooler dysphagia scores and dADL were significantly decreased after treatment. 11 patients (18.3%) experienced grade ≥3 AEs. Compared to PD-L1-Low patients, PD-L1-High patients had a significantly higher ratio of PR. During therapy, the tumor mutation burden (TMB) and tumor neoantigen burden (TNB) were significantly decreased in patients with PR. Differential clonal evolution within tumors was demonstrated by analysis of intratumoral heterogeneity. Transcriptome analyses revealed that the infiltration of CD4+ T lymphocytes at baseline was associated with clinical outcome. During therapy, CD8+ T cells and CD4+ T cells were increased in all patients; however, exhausted cells, nTregs and iTregs were significantly increased in patients with non-MPR. Protein analyses revealed that the levels of IFN-γ, Gal.1 and LAMP3 can predict the clinical benefit. In addition, the expression of CD83, TNFRSF4, TNFSF14, VEGFR2, ADA, ARG1, and HO-1 was associated with serious AEs. More importantly, the integration of CD4+ T cells with plasma protein of IFN-γ, Gal.1 or LAMP3 could further distinguish responders from non-responders. Interpretation: In this study, neoadjuvant therapy with toripalimab, nab-paclitaxel and S-1 was less toxic and showed promising antitumor activity in patients with resectable ESCC. Changes in the genome, transcriptome, PD-L1 expression and serum proteins were comprehensively analyzed and correlated with clinical outcomes, which provides insight into the mechanism of action of toripalimab combined with nab-paclitaxel and S-1 in patients with ESCC. Funding: This study was funded by Major projects of the ministry of science and technology of the 13th five-year plan of China [grant number: 2018ZX09201013].

Abstract Background With the rise of immunotherapy based on cancer neoantigen, identification of neoepitopes has become an urgent problem to be solved. The TP53 R273C mutation is one of the hotspot mutations of TP53, however, the immunogenicity of this mutation is not yet clear. The aim of this study is to identify potential epitopes for p53R273C mutant. Methods In this study, bioinformatic methods, peptide exchange assay, and peptide‐immunized human leukocyte antigen (HLA) transgenic mouse model were used to explore the immunogenicity of this mutation. Results Peptides with higher affinity to common HLA‐A alleles (A*11:01, A*02:01) were discovered by computational prediction. All the 8–11 mer peptides contain the mutation site were synthesized and soluble peptides were used in the peptide exchange assay. However, the exchange efficiencies of these predicted peptides to HLAs were lower. Fortunately, other peptides with higher exchange efficiency were discovered. Then, the immunogenicity of these peptides was validated with the HLA‐A2 transgenic mice model. Conclusion We identified three potential neoepitopes of p53R273C for HLA‐A*02:01, one potential neoepitope for HLA‐A*11:01 and no neoepitope for HLA‐A*24:02.

BackgroundImmune checkpoint inhibitors (ICIs) have changed the treatment landscape of several cancer types. However, data are lacking with regard to the clinical responsiveness of ICIs in patients with advanced non-small cell lung cancer (NSCLC) after standard first-line chemotherapy. Therefore, we aimed to evaluate the clinical efficacy of ICI alone or in combination with chemotherapy for patients with advanced NSCLC after first-line platinum-based chemotherapy.MethodsWe retrospectively collected patients with confirmed advanced NSCLC who underwent ICI monotherapy or ICI plus chemotherapy after first-line platinum-based chemotherapy between January 2018 and December 2020. A propensity score matching analysis was used to balance baseline characteristics between the two treatment groups. Kaplan-Meier methods and multivariable Cox regressions were used for survival analyses.ResultsAmong 832 eligible patients, 222 received ICI monotherapy and 610 received ICI plus chemotherapy. The median overall survival (OS) of patients who received ICI plus chemotherapy was 16.0 months compared with 13.1 months in patients who received ICI monotherapy (HR: 0.64, 95% CI: 0.49-0.85, P = 0.002). After 1:1 propensity score matching, all baseline characteristics were well-balanced between the two treatment groups. Patients who received ICI plus chemotherapy had significantly longer OS than those who received ICI monotherapy (NR vs. 13.1 months, HR: 0.50, 95% CI: 0.34-0.71, P < 0.001). Meanwhile, the median time to treatment discontinuation was 4.4 months in the ICI-chemo group and 3.5 months in the ICI-mono group (HR: 0.72, 95% CI: 0.58-0.89, P = 0.002). The multivariate analysis indicated that treatment regimen was an independent prognostic factor for OS (HR: 0.488, 95% CI: 0.337-0.707, P < 0.001). Moreover, a nomogram that integrated both treatment regimens and clinicopathological factors was created for survival prediction.ConclusionOur study indicated that patients with advanced NSCLC who received ICI plus chemotherapy after first-line platinum-based chemotherapy tended to have longer OS than those who received ICI monotherapy. The multivariate analysis showed that treatment regimen was an independent prognostic factor for OS. Future prospective studies are needed to confirm these findings.

Background: Icaritin is a natural product with a wide range of anti-tumor effects. However, its anti-tumor mechanism has not been thoroughly studied. This study examined the inhibitory effect of icaritin on nasopharyngeal cancer and its underlying mechanism using network pharmacology along with in vivo and in vitro experiments.Methods: MTT and clone formation assays were used to detect the effects of icaritin on the viability and proliferation of nasopharyngeal carcinoma cells, followed by the construction of a HONE1 xenograft tumor model to evaluate the anti-tumor efficacy of icaritin in vivo. A public database was used to predict prospective targets, built a protein-protein interaction (PPI) network, and analyze gene enrichment and biological processes. Based on network pharmacological data, cell cycle-related proteins were identified using western blotting. Besides, cell cycle distribution, apoptosis, and intracellular reactive oxygen species (ROS) generation were identified using flow cytometry. In addition, SA-β-Gal staining was performed to detect cellular senescence, and western blotting was performed to detect the expression of P53, P21, and other proteins to verify key signaling pathways.Results: Icaritin effectively inhibited the viability and proliferation of nasopharyngeal carcinoma cell lines and showed good anti-tumor activity against HONE1 nasopharyngeal carcinoma cells in vivo. Key protein targets, including AKT1, HSP90AA1, CDK4, CCND1, and EGFR, were screened using PPI network topology analysis. GO and KEGG analysis revealed that the cell cycle, p53 signaling, and cell senescence pathways may be the main regulatory pathways. Flow cytometry and western blot experiments showed that icaritin caused S-phase arrest and promoted an increase in ROS. SA-β-Gal staining showed that icaritin significantly induced cellular senescence, and western blotting showed that the expression of senescence-related proteins p53 and P21 increased significantly. Moreover, inhibition of ROS levels by N-Acetylcysteine (NAC) enhanced cell viability, reversed cellular senescence and reduced cellular senescence-associated protein expression.Conclusion: The results of network pharmacological analysis and in vivo and in vitro experiments showed that icaritin effectively inhibited the growth of nasopharyngeal carcinoma cells, promoted ROS production, induced cellular senescence, and inhibited tumor cells, which are related to the regulation of P53/P21 signal pathway.

Measurable residual disease (MRD) positivity before haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an independent prognostic factor in determining outcomes in patients with B-cell acute lymphoblastic leukemia (ALL). In this study, we conducted a parallel comparison of the efficacy and safety in patients with suboptimal MRD response after reinduction who underwent haplo-HSCT after chimeric antigen receptor T-cell (CAR-T) therapy or chemotherapy. Forty B-cell ALL patients who relapsed after first-line chemotherapy and with an MRD ≥0.1% after reinduction were analyzed. The median pre-HSCT MRD in the CAR-T group (n = 26) was significantly lower than that in the chemotherapy group (n = 14) (0.009% vs. 0.3%, p = 0.006). The CAR-T group exhibited a trend toward improved 3-year leukemia-free survival and a significantly improved 3-year overall survival compared to the chemotherapy group [71.8% (95% confidence interval (CI): 53.9–89.6) vs. 44.4% (95% CI: 15.4–73.4), p = 0.19 and 84.6% (95% CI: 70.6–98.5) vs. 40.0% (95% CI: 12.7–67.2), p = 0.008; respectively]. Furthermore, no increased risk of graft-versus-host disease, treatment-related mortality, or infection was observed in the CAR-T group. Our study suggests that CAR-T therapy effectively eliminates pre-HSCT MRD, resulting in better survival in the context of haplo-HSCT.

Abstract Backgrounds Urothelial carcinoma (UC) is the most common genitourinary malignancy in China. In this study, we surveyed the genomic features in Chinese UC patients and investigated the concordance of genetic alterations between circulating tumor DNA (ctDNA) in plasma and matched tumor tissue. Materials and methods A total of 112 UC patients were enrolled, of which 31 were upper tract UC (UTUC) and 81 were UC of bladder (UCB). Genomic alterations in 92 selected genes were analyzed by targeted next-generation sequencing. Results In the study cohort, 94.64, 86.61 and 62.50% of patients were identified as having valid somatic, oncogenic and actionable somatic alterations, respectively. The most frequently altered genes included TP53, KMT2D, KDM6A, FAT4, FAT1, CREBBP and ARID1A. The higher prevalence of HRAS (22.0% vs 3.7%) and KMT2D (59.26% vs 34.57%) was identified in UTUC than in UCB. Comparisons of somatic alterations of UCB and UTUC between the study cohort and western cohorts revealed significant differences in mutant prevalence. Notably, 28.57, 17.86 and 47.32% of the cases harbored alterations in FGFRs, ERBBs and DNA damage repair genes, respectively. Furthermore, 75% of the patients carried non-benign germline variants, but only two (1.79%) were pathogenic. The overall concordance for genomic alterations in ctDNA and matched tumor tissue was 42.97% (0–100%). Notably, 47.25% of alterations detected in ctDNA were not detected in the matched tissue, and 54.14% of which were oncogenic mutations. Conclusions We found a unique genomic feature of Chinese UC patients. A reasonably good concordance of genomic features between ctDNA and tissue samples were identified.

Purpose: With the progress of cancer immunotherapy, hotspot mutations of common oncogenes and tumor suppressors are becoming new potential therapeutic targets. TP53 R273C mutation is one of the hotspot mutations of TP53, and it has a higher frequency in low-grade glioma (LGG). However, the function of this mutation and its prognostic significance in LGG are not still clear.Methods: To address this question, RNA sequencing, clinical, and SNP data of LGG patients from the TCGA database were downloaded. The Kaplan–Meier (KM) method was used for survival analysis. Immune cell populations in this cohort were assessed via the MCP counter and CIBERSORT. DNA damage/repair scores were calculated by GSVA analysis. WGCNA was conducted to identify genes related to TMB.Results: In the context of IDH1/2 mutation, LGG patients with TP53 R273C mutation had worse prognosis than other mutation types and wild types. This conclusion is still valid in LGG patients who had received chemotherapy or radiotherapy. Considering the 1p19q codeletion status, it was found that patients with both R273C mutation and 1p19q non-codeletion had the worst prognosis. Further analysis showed that LGG patients with TP53 R273C mutation had higher M2 macrophage infiltration and tumor mutation burden (TMB) than that of TP53 wild-type LGG patients, and higher TMB indicates poor prognosis in LGG patients. Furthermore, we identified genes which could be associated with higher M2 macrophage infiltration and TMB in LGG patients with TP53 R273C mutation.Conclusion: The study indicates that TP53 R273C mutation is very likely oncogenic and may be used as an indicator of the prognosis of LGG.

Objective: Angiogenesis plays a vital role in tumor growth and metastasis. Here, we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A (VEGFA ) at the transcriptional level to treat triple-negative breast cancer (TNBC). Methods: We used a cell-based seryl tRNA synthetase (SerRS) promoter-driven dual-luciferase reporter system to screen an in-house library of 384 naturally occurring small molecules and their derivatives to find candidate molecules that could upregulate the expression of SerRS, a potent transcriptional repressor of VEGFA. The levels of SerRS and VEGFA were examined by quantitative RT-PCR (qRT-PCR), western blotting, and/or ELISAs in TNBC cells after candidate molecule administration. Zebrafish, the Matrigel plug angiogenesis assay in mice, the TNBC allograft, and xenograft mouse models were used to evaluate the in vivo anti-angiogenic and anti-cancer activities. Furthermore, the potential direct targets of the candidates were identified by proteomics and biochemical studies. Results: We found the most active compound was 3-(4-methoxyphenyl) quinolin-4(1H)-one (MEQ), an isoflavone derivative. In TNBC cells, MEQ treatment resulted in increased SerRS mRNA (P < 0.001) and protein levels and downregulated VEGFA production. Both the vascular development of zebrafish and Matrigel plug angiogenesis in mice were inhibited by MEQ. MEQ also suppressed the angiogenesis in TNBC allografts and xenografts in mice, resulting in inhibited tumor growth and prolonged overall survival (P < 0.05). Finally, we found that MEQ regulated SerRS transcription by interacting with MTA2 (Metastasis Associated 1 Family Member 2). Conclusions: Our findings suggested that the MTA2/SerRS/VEGFA axis is a drug-treatable anti-angiogenic target, and MEQ is a promising anti-tumor molecule that merits further investigation for clinical applications.

ObjectiveThis study aims to assess the efficacy and safety of penpulimab (a humanized anti-PD-1 IgG1 antibody) with anlotinib in the first-line treatment of Chinese patients with uHCC.MethodsIn this open-label multicenter phase Ib/II trial, patients with histologically or cytologically confirmed uHCC, without previous systemic treatment, aged 18–75 years old, classified as BCLC stage B (not amenable for locoregional therapy) or C, with Child–Pugh score ≤7 and ECOG performance status ≤1 were enrolled. Patients received penpulimab [200 mg intravenous (i.v.) Q3W] and oral anlotinib (8 mg/day, 2 weeks on/1 week off). The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, disease control rate (DCR), progression-free survival (PFS), time to progression (TTP), duration of response (DoR), and overall survival (OS). This trial is registered with ClinicalTrials.gov (NCT04172571).ResultsAt the data cutoff (December 30, 2020), 31 eligible patients had been enrolled and treated with a median follow-up of 14.7 months (range, 1.4–22.1). The ORR was 31.0% (95% CI, 15.3–50.8%), and the DCR was 82.8% (95% CI, 64.2–94.2%). The median PFS and TTP for 31 patients were 8.8 months (95% CI, 4.0–12.3) and 8.8 months (95% CI, 4.0–12.9) respectively. The median OS was not reached; the 12-month OS rate was 69.0% (95% CI, 48.9–82.5%). Only 19.4% (6/31) of patients had grade 3/4 treatment-related adverse events (TRAEs).ConclusionPenpulimab plus anlotinib showed promising anti-tumor activity and a favorable safety profile as first-line treatment of patients with uHCC.

BackgroundProstate cancer (PCa) is among the leading causes of cancer mortality. Dicycloplatin is a newer generation platinum-based drug that has less side effects than cisplatin and carboplatin. However, its effects in PCa is mixed due to lack of appropriate stratifying biomarkers. Aiming to search for such biomarkers, here, we analyze a group of PCa patients with different responses to dicycloplatin.MethodsWe carried out whole-exome sequencing on cell-free DNA (cfDNA) and matched leukocyte DNA from 16 PCa patients before treatment with dicycloplatin. We then compared the clinical characteristics, somatic mutations, copy number variants (CNVs), and mutational signatures between the dicycloplatin-sensitive (nine patients) and dicycloplatin-resistant (seven patients) groups and tested the identified mutations, CNV, and their combinations as marker of dicycloplatin response.ResultsThe mutation frequency of seven genes (SP8, HNRNPCL1, FRG1, RBM25, MUC16, ASTE1, and TMBIM4) and CNV rate of four genes (CTAGE4, GAGE2E, GAGE2C, and HORMAD1) were higher in the resistant group than in the sensitive group, while the CNV rate in six genes (CDSN, DPCR1, MUC22, TMSB4Y, VARS, and HISTCH2AC) were lower in the resistant group than in the sensitive group. A combination of simultaneous mutation in two genes (SP8/HNRNPCL1 or SP8/FRG1) and deletion of GAGE2C together were found capable to predict dicycloplatin resistance with 100% sensitivity and 100% specificity.ConclusionWe successfully used cfDNA to monitor mutational profiles of PCa and designed an effective composite marker to select patients for dicycloplatin treatment based on their mutational profile.

Dynamic changes of the peripheral T cell receptor (TCR) and soluble receptors and ligands (sRLs) have the potential to be used as biomarkers to monitor the evolution of the immune system in tumor patients undergoing immunotherapy. These functional biomarkers could be used to predict immune response to treatment with immune checkpoint inhibitors (ICIs) and to provide high-value information on the immune function status of cancer patients, thereby helping physicians to make effective clinical decisions. We collected paired pre- and post-treatment peripheral blood samples from 31 solid tumor patients treated with ICIs. TCR and sRL status were investigated using next-generation sequencing and magnetic bead panels. We found that the diversity of the dominant TCR clone at baseline was correlated with durable clinical benefit in patients receiving single-agent treatment. The D50 index, the diversity from the cumulative 50% of the total complementary determinant region 3, was obtained during treatment. A significant difference in progression-free survival was demonstrated between the D50 high and D50 low groups. This result was validated in an independent cohort. A signature including soluble immune checkpoint proteins (sICPs) was identified. Upregulation of the signature during treatment was correlated with durable clinical benefit. All these results indicate that a novel biomarker based on peripheral TCR and sICPs has the potential to be used in prognostic prediction and for rapid determination of therapeutic outcomes in patients treated with immune checkpoint inhibitors.

Abstract Background Tumor mutation burden (TMB), DNA mismatch repair deficiency (dMMR), microsatellite instability (MSI), and PD‐L1 amplification (PD‐L1 AMP) may predict the efficacy of the PD‐1/PD‐L1 blockade. With the broadening landscape of immunotherapy use, it is important to identify patients who are likely to benefit from the therapy. This study aimed to characterize the distributions of these biomarkers and explore the relationships among these biomarkers for Chinese patients with cancer. Methods In this study, we examined the aforementioned biomarkers in more than 1000 Chinese patients with cancer. These biomarkers were determined based on whole‐exome sequencing (WES) of tumor/blood samples. Results Of the 953 samples from Chinese cancer patients assessed in this study, 35% exhibited high TMB (TMB‐H), 4% were positive for high MSI (MSI‐H), dMMR occurred in 0.53%, and PD‐L1 AMP was positive in 3.79%. We found higher rates of TMB‐H among hepatocellular carcinoma, breast cancer, and esophageal cancer patients than was reported for The Cancer Genome Atlas (TCGA) data. Lung cancer patients with EGFR mutations had significantly lower TMB values than those with wild‐type EGFR, and increased TMB was significantly associated with dMMR in colorectal cancer (CRC). The frequency of tumors with MSI‐H was the highest in CRC and gastric cancer. PD‐L1 AMP occurred most frequently in lung squamous cell carcinoma and HER2‐positive breast cancer. While MSI and dMMR are associated with higher mutational loads, correlations between TMB‐H and other biomarkers, between MSI‐H and dMMR, and between PD‐L1 AMP and other biomarkers were low, indicating different underlying causes of the four biomarkers. Conclusion The results reveal the frequency of these biomarkers in different malignancies, with potential implications for PD‐1/PD‐L1 blockade use for Chinese patients with cancer.

Abstract Background Lung adenocarcinoma in young adults is a rare entity with the oncogenic genetic alterations associated being poorly understood. In the present study, the effect of genetic alterations in lung adenocarcinoma patients diagnosed in young patients is reported. Methods Twenty young lung adenocarcinoma patients (age years: median: 33.5, range: 24‐36) were enrolled in the current study and 24 patients who were at common age of the disease onset (age years: median: 61.5, range: 52‐79) were selected for comparison. Paraffin sections of lung adenocarcinoma were analyzed using the whole‐exome sequencing platform. Results Similar number of somatic mutations per tumor were found in the young patients and their older counterparts. Although no age‐related differences were detected in the numbers of lung adenocarcinoma patients harboring well‐known gene variants, mutations in FRG1 and KMT2C were associated with a younger age especially after correcting for tobacco smoking and sex (FRG1: P = 0.027, KMT2C: P = 0.046). Five genetic variants showed higher alteration frequencies in young patients compared to the unclassified East Asian population, suggesting these mutations as disease‐related hereditary germline variants. Conclusions These results suggest different characteristics of lung adenocarcinoma between the young and the patients at common age of onset. Young patients with lung adenocarcinoma have a distinctly unique prevalence of oncogenic genetic alterations.

Abstract The main aim of this study is to investigate whether baseline lactate dehydrogenase (LDH) is associated with the clinical outcome of non small‐cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). We searched Pubmed, the Cochrane Central library and Embase for peripheral blood biomarker of LDH in advanced NSCLC patients treated with ICIs. We extracted the hazard ratio (HR) with 95% confidence interval (CI) for the progression free survival (PFS) and overall survival (OS) and performed meta‐analysis of HR. Pooled estimates of treatment outcomes were calculated by stata 15.1. Six studies with 1136 patients were included in this study. The pooled results of univariate analysis suggested that an elevated pretreatment LDH level was correlated with significant shorter PFS (HR = 1.53, 95% CI 1.27‐1.83, P

Lung cancers, the leading cause of cancer mortality worldwide, are characterized by a high metastatic potential. Growing evidence reveals that Spindlin 1 (SPIN1) is involved in tumor progression and carcinogenesis. However, the role of SPIN1 in non-small-cell lung cancer (NSCLC) and the molecular mechanisms underlying SPIN1 in human NSCLC remain undetermined. Here we examined the function of SPIN1 in human NSCLC and found that the expression of SPIN1 was closely correlated with the overall survival and poor prognosis of NSCLC patients. Aberrant regulation of microRNAs (miRNAs) has an important role in cancer progression. We revealed that miR-409 inhibits the expression of SPIN1 by binding directly to the 3′ UTR of SPIN1 using dual-luciferase reporter assays. Overexpression of miR-409 significantly suppressed cell migration, growth, and proliferation by inhibiting SPIN1 in vitro and in vivo. SPIN1 overexpression in miR-409-transfected NSCLC cells effectively rescued the suppression of cell migration, growth, and proliferation regulated by miR-409. miR-409 regulates the PI3K/AKT (protein kinase B) pathway in NSCLC. Moreover, clinical data showed that NSCLC patients with high levels of miR-409 experienced significantly better survival. miR-409 expression was also negatively associated with SPIN1 expression. Taken together, these findings highlight that the miR-409/SPIN1 axis is a useful pleiotropic regulatory network and could predict the metastatic potential in NSCLC patients early, indicating the possibility that miR-409 and SPIN1 might be attractive prognostic markers for treating NSCLC patients. Keywords: non-small lung cancer, NSCLC, miR-409, SPIN1, therapy

Antibodies against checkpoint inhibitors such as anti-programmed cell death protein 1 (PD-1) and its ligand anti-programmed death ligand 1 (PD-L1) have shown clinical efficacy in the treatment of multiple cancers. However, there are only a few studies on biomarkers for these targeted immunotherapies, especially in peripheral blood. We first studied the role of interferon-induced protein-10 (IP10) combined with interleukin-8 (IL-8) in peripheral blood as a biomarker of immune-combined chemotherapy for lung cancer and multiple cancers. We used the high-throughput cytokine detection platform and performed bioinformatics analysis of blood samples from 67 patients with lung cancer and 24 with multiple cancers. We selected the ratio of IP-10 to IL-8 (S2/S0, ratio of changes at 10–12 weeks after treatment to baseline) to predict the response to immunotherapy combined with chemotherapy and evaluate the survival of lung cancer patients and mixed cancer patients. In patients treated with the combination therapy, the specificity and sensitivity of IL-8 and IP10 together as predictors were improved compared with those of IL-8 and IP10 alone. Our conclusion was verified in not only lung cancer but also multiple cancer research cohorts. We then further validated the predictive effect of biomarkers in different histologic types of NSCLC and chemotherapy combined with different PD-1 drug groups. Subsequent validation should be conducted with a larger number of patients. The proposed marker IP10 (S2/S0)/IL-8 (S2/S0), as a predictive immunotherapy biomarker, has broad prospects for future clinical applications in treating patients with multiple intractable neoplasms.

Aim: A prospective investigation of serum thymidine kinase 1 concentration (STK1p) was performed to evaluate its prognostic value in patients with non-small-cell lung carcinoma (NSCLCs). Patients & methods: The STK1p values of 127 patients were determined by an enhanced chemiluminescent dot blot assay. The patients were recruited from March 2011 to December 2017. Results: Kaplan–Meier plot showed that patients with elevated STK1p values had worse overall survival (OS), especially patients of early/middle stages. Multi-variable COX regression showed that STK1p value and combined treatment surgery + chemotherapy were independent prognostic factors for favorable OS. Conclusion: STK1p is helpful in predicting OS of early/middle stages (I–IIIA) NSCLCs patients following a nonrandomized individual adapted treatment, but is may be not recommended in advanced stages (IIIB + IV) of NSCLCs.

BackgroundCombination therapy with immune checkpoint inhibitors (ICIs) and antiangiogenic agents is generally effective and well tolerated and might be effective for metastatic urothelial carcinoma (UC). However, ICI treatment is often associated with unique responses, such as pseudoprogression and ICI-related pneumonitis (CIP), which may influence clinical decision making and affect treatment. Although there have been many studies on the mechanism of pseudoprogression and CIP, the characteristics and relationship of these special events in a clinical setting remain rarely reported.Case PresentationHere, we present a patient with lung metastatic UC who underwent surgery and two lines of chemotherapy. The programmed cell death-1 (PD-1) inhibitor nivolumab and antiangiogenics agent bevacizumab were used as maintenance treatments. The patient experienced pseudoprogression after 2 PD-1 inhibitor cycles. The lesions in both lungs were enlarged on computed tomography (CT) imaging, and treatments were continued for another two cycles, after which the tumor size decreased to below baseline, followed by a durable response. However, after 4 months of pseudoprogression, the patient then developed CIP. The CIP was responsive to glucocorticoid therapy but recurred during ICI rechallenge, leading to the termination of immune therapy. Ultimately, the patient achieved durable, stable disease for over 18 months without further anticancer treatment.ConclusionsOur case shows that pseudoprogression can occur in UC during immunotherapy even when combined with an effective antiangiogenic agent. In addition, pseudoprogression may be correlated with future adverse effects and a durable response. In the management of CIP, early rechallenge with ICIs may lead to CIP recurrence, which could be more severe and needs to be treated early and with appropriate drugs. Clinicians should be aware of atypical responses to ICIs and adjust the treatment plan accordingly.

Background: Recent studies have demonstrated the predictive value of pretreatment neutrophil-to-lymphocyte ratio (NLR) in advanced cancers; however, the role of NLR in patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) remained to be explored. Thus, we aimed to investigate whether pretreatment NLR was associated with the outcomes of advanced NSCLC patients treated with ICIs.Methods: A comprehensive literature research was first conducted in PubMed, the Cochrane Central Library, and Embase for studies that evaluated the association between pretreatment NLR and survival of advanced NSCLC patients with ICIs treatment. We then conducted a retrospective study in Chinese People's Liberation Army (PLA) General Hospital (Beijing, China) to validate these findings.Results: A total of 17 eligible studies with 2,106 patients were included in our meta-analysis, of which, 12 studies reported progression-free survival (PFS), and 13 studies reported overall survival (OS). The pooled results showed that high pretreatment NLR was significantly associated with poorer PFS (HR = 1.44, 95% CI 1.26–1.65; P < 0.001) and OS (HR = 2.86, 95% CI 2.11–3.87; P < 0.001) compared with those with low pretreatment NLR. Subgroup analysis demonstrated that the association between baseline NLR and PFS remained significant except that the cut-off value of NLR was 3 (HR = 1.48, 95% CI 0.93–2.37; P = 0.098) and region of Asia (HR = 1.55, 95% CI 1.00–2.39; P = 0.051). These results were further validated in our retrospective study that patients with pretreatment NLR ≥ 6.0 had shorter PFS (median: 5.0 vs. 9.1 months, HR = 1.39; 95% CI 1.01–1.91; P = 0.02) and OS (median: 10.0 vs. 17.3 months, HR = 1.71; 95% CI 1.18–2.46; P < 0.001) compared with those with NLR < 6.0. The associations between NLR and survival were consistent in subgroup analysis stratified by age, gender, ECOG PS, histology, stage, smoking history, treatment, and prior lines of therapy. Dynamics of NLR (dNLR) that increased ≥3.0 from baseline was also significantly associated with worse PFS (median: 3.1 vs. 9.1 months; P = 0.01) and OS (median: 6.8 vs. 17.0 months; P < 0.0001).Conclusions: Our study demonstrates that pretreatment NLR and dNLR from baseline are associated with the outcomes of advanced NSCLC patients treated with ICIs; however, it warrants further prospective studies.

Abstract Background Immunoscore, as a prognostic tool defined to quantify in situ immune cell infiltrates, appears to be superior to the TNM staging system. In esophageal squamous cell carcinoma (ESCC), no immunoscore has been established; however, in situ tumor immunology is recognized as highly important. Our study aimed to construct a comprehensive immunoprofile for ESCC. Methods The infiltration of four immune cell types (CD8+/CD4+/Foxp3+/CD33+ cells), the expression of both inhibitory (PD-1/PD-L1/Tim-3/LAG-3) and stimulatory checkpoints (OX-40/ICOS), and IDO1 were evaluated by IHC staining and multi-color immunofluorescence in two independent cohorts (95 patients in the primary cohort and 55 patients in the validation cohort). The association with patients’ overall survival was analyzed by the Kaplan-Meier method and the Cox model. Nomogram-based immunoprofile was established using the independent prognostic variables. To determine its predictive accuracy and discriminatory capacity, the C-index and calibration curve were calculated. Results Significant correlation of PD-L1 expression in tumor cells with PD-1+ T cell infiltration was found (P = 0.035), indicating the activation of the inhibitory PD-1/PD-L1 pathway in ESCC cases. More PD-L1+ ICs, Tim-3+ ICs and LAG-3+ ICs were found in the CD8-rich tumor microenvironment, which is in accordance with the feedback nature of immune system. After adjustment by TNM stage, four immune variables including the infiltration of CD8+/Foxp3+/CD33+ cells and the PD-L1 expression by tumor cells were selected to construct a prognostic nomogram. The calibration curves showed good accuracy of the nomogram for survival prediction. To overcome the complexity of applying a nomogram in a clinical setting, a simple immunoprofile was then established according to the points of each factor from the nomogram. Our immunoprofile model could separate same-stage patients into different risk subgroups, and showed superior accuracy for survival prediction than the TNM staging system based on the C-index calculation and ROC analysis. Conclusions Our nomogram-based immunoprofile can provide more accurate prognosis prediction and is an important complement to the TNM staging system for operable ESCC patients.

Abstract A dynamic and mutualistic interaction between tumor cells and tumor microenvironment (TME) promotes the progression and metastasis of solid tumors. Cancer immunotherapy is becoming a major treatment paradigm for a variety of cancers. Although immunotherapy, especially the use of immune checkpoint inhibitors, has achieved clinical success, only a minority of patients exhibits durable responses. Clinical studies directed at identifying appropriate biomarkers and immune profiles that can be used to predict immunotherapy responses are presently being conducted. Combining treatment strategies tailored to cancer‐immune interactions are designed to increase the rate of durable clinical response in patients. It is essential to establish a reasonable tumor classification strategy according to TME to improve cancer immunotherapy. In the current review, a modified classification of TME is proposed, and optimization of TME classification is needed through detailed and integrated molecular characterization of large patient cohorts in the future.

Abstract Background Cancers can survive the oxidative conditions by upregulating nucleoside diphosphate linked moiety X-type motif 1 (NUDT1). However, the mechanisms underlying gastric carcinogenesis and the dys-regulation of NUDT1 in gastric cancer (GC) remain unknown. Our study aimed to explore the role of NUDT1 and its regulatory pathway by miR-485-5p in GC. Methods Gastric cancer tissues and paired noncancerous tissue samples were collected, and the expression level of NUDT1 and miR-485-5p were detected. Two cohorts from The Cancer Genome Atlas (TCGA) database and another cohort from the Tianjin Medical University Cancer Institute and Hospital were further analyzed. Luciferase assays were performed, and the effects of the miR-485-5p/NUDT1 axis on GC cells and normal gastric cells were determined by subsequent experiments. Results We found that the expression of miR-485-5p was clearly repressed in GC tissues, while NUDT1 expression level was dramatically increased. The overexpression of NUDT1 correlated closely with an increase in invasive depth and a decrease in survival in GC patients. MiR-485-5p could directly bind to the 3′UTR of NUDT1 mRNA and induce its degradation, thus down-regulate its expression. The miR-485-5p/NUDT1 axis could lead to the changes of 8-oxo-dG in GC cells. And the increased expression of NUDT1 resulting from the downregulation of miR-485-5p could accelerate cell proliferation and metastasis in GC. However, the growth and migration of normal gastric cells did not depend on the protection of NUDT1, while the overexpression of NUDT1 could promote malignant transition in normal gastric cells. Conclusions MiR-485-5p acts as a tumor suppressor by targeting NUDT1 in GC. The miR-485-5p/NUDT1 axis is involved in the processes of cell growth and cell motility and plays a key role in the tumorigenesis of GC.

CDC25 phosphatases are important cell cycle regulators. Here, the authors show that the LIM domain-containing proteins (for example, FHL1) induce inhibitory CDC25 phosphorylation resulting in radioresistance and that a specific peptide can increase tumour radiosensitivity by increasing CDC25 activity.

Background: Altered immunoresponse is associated with tumorigenesis and cancer progression. This study assessed the levels of tumor-infiltrating CD3 + or CD8 + T lymphocytes and interleukin-2 (IL-2) protein in radically resected non-small cell lung cancer (NSCLC) tissues to predict overall survival (OS) of the patients. Methods: Paraffin-embedded tissue specimens from 129 NSCLC patients were retrospectively collected for immunostaining of CD8 + , CD3 + , and IL-2 expression. Clinicopathological and survival data were collected and analyzed using the Chi-squared test, Kaplan-Meier curves, and the log-rank test or the Cox regression model. Results: The data showed a significant inverse association between CD8 + T lymphocyte levels and IL-2 expression (r = −0.927; P = 0.000) and between the levels of CD8 + and CD3 + T lymphocytes (r = −0.722; P = 0.000), but a positive association between CD3 + T lymphocyte levels and IL-2 expression (r = 0.781; P = 0.000) in NSCLC tissues. Furthermore, the levels of CD3 + and CD8 + T lymphocytes and IL-2 expression were associated with tumor stage (P = 0.023, 0.006, and 0.031, respectively) and the level of CD8 + T lymphocytes was associated with the patient gender (P = 0.024). In addition, the levels of CD8 + T lymphocytes were associated with an unfavorable 5-year OS, whereas patients with high levels of CD3 + T lymphocytes in tumor lesions and IL-2-expressing tumors had significantly better 5-year OS rates than patients with low levels. Conclusions: The levels of CD8 + T cells in tumor lesions and IL-2 expression were both independent predictors of OS for these NSCLC patients. Thus, the detection of tumor-infiltrating CD3 + or CD8 + T lymphocytes and IL-2 expression could be useful to predict the prognosis of radically resected NSCLC patients.

Brain metastasis, a common complication of non-small cell lung cancer (NSCLC) with an incidence rate of 30%-50%, significantly affects the patients’ quality of life. The prognosis of patients of NSCLC with brain metastasis is extremely poor, the average median survival is only 1 m-2 m without treatment. The targeted therapy based on lung cancer driven gene is a new treatment. Besides, the immunotherapy which can enhance the effect of anti-cancer by simulating the immune system is a new approach. The combination of targeted therapy and immunotherapy can greatly benefit patients in clinical work.

Background and objective Due to the various inter-individual differences in the biological characteristics of tumor cells, as well as issues on the efficacy, adverse reactions, and defects of existing drugs, we compared the clinical efficacy and toxicity of pemetrexed and gemcitabine combined with cisplatin for the treatment of previously untreated advanced non-small cell lung cancer (NSCLC). Methods 251 patients were randomly divided into pemetrexed combined with cisplatin group (PP group) with 127 cases and gemcitabine combined with cisplatin group (GP group) with 124 cases. PP group received pemetrexed 500 mg/m2 iv infusion d1 and cisplatin 75 mg/m2 iv infusion d1, whereas GP group received gemcitabine 1,000 mg/m2 iv infusion d1,8 and cisplatin 75 mg/m2 iv infusion d1. The treatment cycle was once every three weeks. In addition, folic acid, vitamin B12, and dexamethasone were administered in both groups. Results The total clinical effective rates in PP group and GP group were 25.20% and 17.74%, respectively. The total efficiencies of non-squamous cell carcinoma were 27.62% and 16.00%. The tumor progression duration in these two groups was 6.5 and 5.6 months, respectively. The median survival time in the two groups was 16.9 and 17.0 months, respectively, with 59.62% and 65.87% survival rates of 1 year and 27.28% and 27.93% survival rates of 2 years, respectively. The total efficacy of non-squamous cell carcinoma in the PP group was significantly higher than that in GP group. The results were statistically significant. However, there were no significant differences in total response rates, tumor progression duration, and median survival rates of 1 and 2 years. The rate of adverse reactions, including white blood cell reduction, lower platelet count, lower hemoglobin, and hair loss in the PP group was significantly lower than that in the GP group. The results were statistically significant. Conclusion The clinical efficacy of pemetrexed and gemcitabine combined with cisplatin for the treatment of previously untreated advanced NSCLC was roughly the same, but the adverse reactions decreased significantly in the PP group compared with those in the GP group. Therefore, pemetrexed combined with cisplatin can be used as a safe and effective drug for clinical first-line treatment for previously untreated NSCLC.

Background and objective The immune function disorder relates closely to the occurrence, metastasis, and prognosis of cancer. T lymphocyte subsets take an important role in immune function. We identified the dynamic changes of the immune system by investigating the levels of T lymphocyte subsets in peripheral blood of lung cancer patients with advanced stage adenocarcinoma undergoing first line chemotherapy. The results aided the search for rational chemo-immunotherapy strategies in lung cancer treatment. Methods Samples from 49 patients with pathologically demonstrated advanced stage adenocarcinoma cell lung cancer were compared with those from 33 healthy donors. Subsequently, the patients were separately treated with Docetaxol-based or Pemetrexed-based therapy. Peripheral blood samples at different time points after therapy were analyzed by flowcytometry. The lymphocyte subsets of the total lymphocytes were compared. Independent sample t test was used for the quantitative data analysis. Results The percentage of CD3+, CD3+CD4+, CD4+CD25+ cells of the lung cancer patients significantly varied from those of the healthy donors, the P values are 0.012, 0.034 and 0.006 separately. The CD3+ and CD3+CD4+ levels increased significantly on the 4th and 7th-10th day post-chemotherapy, which return to normal levels on the 21th day. The CD3+ level increased significantly both in the treatment group on all time points, while the CD3+, CD3+CD4+, CD4+/CD8+ levels significantly increased and the CD3+CD8+, CD8+CD28- levels significantly decreased on the 4th day in Pemetrexed group. The CD3+CD4+ levels increased significantly on the 4th and 7th-10th day and the CD3+CD8+, CD8+CD28- levels decreased on the 4th day in partial response group. Conclusion The immune function of advanced stage adenocarcinoma cell lung cancer patients was evidently suppressed, and was restored at the 4th day, followed by a reduction at the 21st day after chemotherapy. On the 4th day, Pemetrexed showed better effect on the immune system. The change of immune system post-chemotherapy could be related with the prognosis.

Overall, gastric cancer prognosis remains poor. Detailed characterization of molecular markers that govern gastric cancer pathogenesis is warranted to establish innovative therapeutic options. HIF-1α overexpression has been linked to poor gastric cancer prognosis. However, though researched for years, the prognostic role of HIF-1α in gastric cancer is still controversial. Hence, the objective of the present study was to analyze the prognostic values of HIF-1α, TGF-β, VEGF and pERK1/2 in gastric cancer patients following gastrectomy.This study included 446 patients with confirmed gastric cancer who underwent gastrectomy in a single Chinese Cancer Center between 2005 and 2006. Clinicopathologic features, as well as immunohistochemical analysis of TGF-β, HIF-1α, VEGF and pERK1/2 were determined. Long-term survival of these patients was analyzed using univariate and multivariate analyses.HIF-1α overexpression was more frequent in patients with hepatic metastases (71.6% versus 43.0% in those without hepatic metastases, P = 0.000, χ2 = 23.086) and more frequent in patients with peritoneum cavity metastasis (62.3% versus 43.0% in those without such metastasis, P = 0.000, χ2 = 13.691). In univariate analysis, patients with HIF-1α overexpression had a shorter disease-free survival (DFS) and overall survival (OS) than patients with weak-expression (DFS: NA VS. 16.8 m, P = 0.000, χ2 = 74.937; OS: NA VS. 25.5 m, P = 0.000, χ2 = 90.594). Importantly, HIF-1α overexpression was a promising prognostic marker for poor survival by multivariate analysis (DFS: HR 2.766, 95%CI 2.136-2.583, P = 0.000; OS: HR 3.529, 95%CI 2.663-4.667, P = 0.000).HIF-1α overexpression could be considered a useful independent prognostic biomarker in gastric cancer after gastrectomy, and is correlated to both a poor overall survival and disease-free survival in these patients. HIF-1α expression can be used to stratify patients at higher risk for poor prognosis, and is potentially an important therapeutic target in gastric cancer patients.